Abstract
Endogenous retroviruses (ERVs), the remnants of retroviral infections in the germ line, occupy ~8% and ~10% of the human and mouse genomes, respectively, and affect their structure, evolution, and function. Yet we still have a limited understanding of how the genomic landscape influences integration and fixation of ERVs. Here we conducted a genome-wide study of the most recently active ERVs in the human and mouse genome. We investigated 826 fixed and 1,065 in vitro HERV-Ks in human, and 1,624 fixed and 242 polymorphic ETns, as well as 3,964 fixed and 1,986 polymorphic IAPs, in mouse. We quantitated >40 human and mouse genomic features (e.g., non-B DNA structure, recombination rates, and histone modifications) in ±32 kb of these ERVs’ integration sites and in control regions, and analyzed them using Functional Data Analysis (FDA) methodology. In one of the first applications of FDA in genomics, we identified genomic scales and locations at which these features display their influence, and how they work in concert, to provide signals essential for integration and fixation of ERVs. The investigation of ERVs of different evolutionary ages (young in vitro and polymorphic ERVs, older fixed ERVs) allowed us to disentangle integration vs. fixation preferences. As a result of these analyses, we built a comprehensive model explaining the uneven distribution of ERVs along the genome. We found that ERVs integrate in late-replicating AT-rich regions with abundant microsatellites, mirror repeats, and repressive histone marks. Regions favoring fixation are depleted of genes and evolutionarily conserved elements, and have low recombination rates, reflecting the effects of purifying selection and ectopic recombination removing ERVs from the genome. In addition to providing these biological insights, our study demonstrates the power of exploiting multiple scales and localization with FDA. These powerful techniques are expected to be applicable to many other genomic investigations.
Highlights
Endogenous Retroviruses (ERVs) are Class I Transposable Elements (TEs) considered to be remnants of germ-line retrovirus infections inherited by the generations [1]
The distributions of in vitro and polymorphic ERVs are only marginally influenced by selection and provide a more accurate view of integration preferences
We considered 1,866 ETns (242 polymorphic and 1,624 fixed) and 5,950 IAPs (1,986 polymorphic and 3,964 fixed) detected genome-wide by Zhang and colleagues [25]; elements were considered to be fixed if they were shared among four mice strains, and polymorphic if they were present in the C57BL/6J strain but not in the other three strains
Summary
Endogenous Retroviruses (ERVs) are Class I Transposable Elements (TEs) considered to be remnants of germ-line retrovirus infections inherited by the generations [1]. As all Class I TEs, ERVs transpose via an RNA intermediate, i.e. they “retrotranspose”. Because they possess Long Terminal Repeats (LTRs), they are known as LTR-retrotransposons. Depending on the similarity of their gene content to that of certain retroviruses, ERVs are classified as Gammaretrovirus-, Betaretrovirus-, and Spumaretrovirus-like [1,2,3]. Full-length ERVs possess three retroviral coding genes (i.e. gag, pol, and env) and LTR flanking sequences [4]]. The internal genes are deleted by recombination of LTRs, converting ERVs into soloLTRs [5,6]
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